In the United States, 1.4 million people each year suffer a traumatic brain injury. Of those who survive, 80-90,000 people per year experience long-term disabilities, often including retrograde amnesia and deficits in learning and memory due to hippocampal neuronal cell loss. Bilateral loss of hippocampal neurons has been observed in 85% of fatal human head injury cases. Within the hippocampus, pyramidal neurons are particularly vulnerable to brain injury in humans as well as experimental animal models of TBI. Although the cognitive problems are among the most long-lasting and debilitating outcomes in patients, no neuroprotective therapy is available for this type of damage in human patients. Therefore, the need for the development of therapeutic strategies aiming at protecting these cells is critical. In the previous grant cycle, we identified a mammalian neurotrophin (NT4/5) that is neuroprotective for pyramidal neurons. A related neurotrophin, brain-derived neurotrophic factor (BDNF) was ineffective. The purpose of this proposal is to evaluate in detail the efficacy and mechanism of NT4/5-mediated hippocampal neuroprotection. Our proposed experiments will determine the functional benefit of this new theraputic molecule as well as the limitations associated with its use. Our Central Hypothesis is: NT4/5 rescue of CAS pyramidal neurons after TBI improves hippocampal function via upregulation of a specific set of neuroprotective genes. We will investigate this hypothesis by: (1) Determining whether NT4/5 treatment improves hippocampal function after experimental traumatic brain injury; (2) Determining the mechanism of NT4/5-mediated neuroprotection by examining 11 candidate genes upregulated by NT4/5 but not by BDNF; and (3) Determining the critical parameters for NT4/5 rescue of hippocampal neurons. We will use multiple levels of analysis (molecular, cellular, circuit and behavioral) to gain a detailed understanding of the mechanism of NT4/5 neuroprotection. These findings will provide insight for developing more specific therapies to ameliorate memory loss in TBI patients.